The long term goal of this proposal is to investigate the regulation of mood and motivation by hypothalamic feeding systems. Disruptions in appetite and body weight regulation are among the most important concerns to patients with mood disorders. Metabolic diseases including obesity, type II diabetes mellitus and heart disease are all much more common in patients with major depression, bipolar disorder, and post-traumatic stress disorder. Despite substantial clinical evidence that links mood disorders and feeding, very little is known about the underlying neurobiological mechanism that regulates these two systems. Recently we have demonstrated that restriction of calorie intake can produce dramatic anxiolytic-like and antidepressant-like responses in mice. Additionally, mice subjected to chronic social stress not only develop depressive symptoms, but also display increased food intake, increased adipose tissue, and elevated insulin and triglyceride levels. Preliminary analysis of these chronically stressed mice demonstrates central leptin resistance and decreased melanocortin signaling. Administration of a melanocortin agonist decreases body weight and food intake but worsens depressive symptoms. Based upon these preliminary data we propose a hypothesis that disruption of melanocortin signaling by chronic stress may help alleviate mood symptoms but at the cost of metabolic side effects. In order to test this hypothesis we have obtained two mouse lines. One line expresses green fluorescent protein under the control of the melanocortin receptor 4 promoter. The second line prevents expression of the melanocortin receptor 4 unless exposed to Cre-recombinase. With these two powerful tools we propose the following Specific Aims: 1. To determine if melanocortin receptor 4 neurons in the ventral striatum innervate the lateral hypothalamic area using our unique melanocortin receptor 4 -GFP mouse. 2. To determine if genetic blockade of melanocortin receptor 4 produces anxiolytic-like and antidepressant-like behaviors. 3. To determine if selective re-expression of melanocortin receptor 4 in the nucleus accumbens is sufficient to restore normal anxiety and depression responses in melanocortin receptor 4 null mice. PUBLIC HEALTH RELEVANCE: Patients suffering from major depression, bipolar disorder, and post-traumatic stress disorder have much higher rates of obesity and related diseases such as diabetes and heart disease. The purpose of this research is to investigate the link between mood disorders and feeding and body weight regulation.